Olanzapine i.e. 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine of Formula I is an antipsychotic drug.
Olanzapine is an antagonist of dopamine D-1 and D-2 receptors, and in addition has antimuscarinic anticholinergic properties and antagonist activity at noradrenergic α-receptors. These properties indicate that the compound is a potential neuroleptic with relaxant, anxiolytic and anti-emetic properties, and may be useful in treating psychotic conditions such as, but not limited to, schizophrenia, schizophreniform diseases and mania. At lower doses the compound is indicated for use in the treatment of mild anxiety states.
In view of the importance of Olanzapine as an antipsychotic compound, several synthetic methods have been reported in the literature, which are as summarized below:
Olanzapine was first disclosed in U.S. Pat. No. 5,229,382. This patent does not refer to any specific polymorphic Form of Olanzapine. U.S. Pat. No. 5,736,541 patent claims Form II of Olanzapine. This patent also designated that the product obtained according to the process described in U.S. Pat. No. 5,229,382 is Form I.
U.S. Pat. No. 5,229,382 discloses a process in which the crude Olanzapine is prepared in acetonitrile at boiling temperatures.
U.S. Pat. No. 5,703,232 discloses a process to prepare Form I. The process comprising, suspending technical grade Olanzapine in acetone or tetrahydrofuran or ethyl acetate or t-butanol and heated to 60° C. while stirring the mixture was maintained for 30 min. The mixture was cooled to about 25° C. The resulting product was isolated using vacuum filtration. The product identified as Form I. In the same patent another process is described which comprises, dissolving alcoholate solvate of Olanzapine in different solvents to prepare Form I.
U.S. Pat. No. 5,637,584 discloses a process to prepare anhydrous Form I from Olanzapine methylene chloride solvate. The process comprises, drying or azeotroping the methylene chloride solvate and recrystallizing the material in an appropriate solvent in the presence of a Form I seed crystal to provide the desired Form I Olanzapine.
US 2004/0048854 claims a process to prepare Olanzapine Form I, which comprises reacting 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazpine HCl and 1-methylpiperazine in an aprotic high boiling solvent or mixtures thereof (dimethyl sulfoxide, dimethylforamide, a mixture of dimethyl sulfoxide and toluene, or a mixture of dimethylforamide and toluene) at a temperature of between about 90 to 130° C.; purifying the product in acidic medium (acetic acid); basifying the product (sodium hydroxide) to a pH of between 7.5-9; and extracting the product using a low boiling organic solvent (diethylether, dichloromethane, dichloroethane, chloroform, ethyl acetate, other low polar ketonic solvents, and mixtures thereof) and Form I isolated.
US 2004/0067936 A1 claims a process to prepare Olanzapine Form I from Olanzapine dihydrate-I or Olanzapine monohydrate-I or Olanzapine Form II. The process comprising stirring from Olanzapine dihydrate-I or Olanzapine monohydrate-I or Olanzapine Form II in dichloromethane at reflux to obtain a clear solution. Then to the resulting solution carbon was added, followed by filtration and cooling the filtrate to 0-5° C. and stirring for 60-90 min. Then solid was separated and washed, and dried at 60-70° C. to a constant weight.
However, with the above reported processes, we noticed that Form I is not formed consistently. Hence, there is a need to develop a solvent/solvent system which gives Form I consistently.